tbuckley/cabot-search huggingface dataset:
Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors
Authors: Deepti Gadi, Stephen P. Martindale, Pui Yan Chiu, Jasneet Khalsa, Pei-Hsuan Chen, Stacey M. Fernandes, Zixu Wang, Svitlana Tyekucheva, John-Hanson Machado, David C. Fisher, Philippe Armand, Matthew S. Davids, Scott Rodig, Barbara Sherry, Jennifer R. Brown
Journal: Blood Cancer Journal (2023)

PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.
Engineering 3D micro-compartments for highly efficient and scale-independent expansion of human pluripotent stem cells in bioreactors
Authors: Philippe J.R. Cohen, Elisa Luquet, Justine Pletenka, Andrea Leonard, Elise Warter, Basile Gurchenkov, Jessica Carrere, Clément Rieu, Jerome Hardouin, Fabien Moncaubeig, Michael Lanero, Eddy Quelennec, Helene Wurtz, Emilie Jamet, Maelle Demarco, Celine Banal, Paul Van Liedekerke, Pierre Nassoy, Maxime Feyeux, Nathalie Lefort, Kevin Alessandri
Journal: Biomaterials (2023)

Human pluripotent stem cells (hPSCs) have emerged as the most promising cellular source for cell therapies. To overcome the scale-up limitations of classical 2D culture systems, suspension cultures have been developed to meet the need for large-scale culture in regenerative medicine. Despite constant improvements, current protocols that use microcarriers or generate cell aggregates only achieve moderate amplification performance. Here, guided by reports showing that hPSCs can self-organize in vitro into cysts reminiscent of the epiblast stage in embryo development, we developed a physio-mimetic approach for hPSC culture. We engineered stem cell niche microenvironments inside microfluidics-assisted core-shell microcapsules. We demonstrate that lumenized three-dimensional colonies significantly improve viability and expansion rates while maintaining pluripotency compared to standard hPSC culture platforms such as 2D cultures, microcarriers, and aggregates. By further tuning capsule size and culture conditions, we scale up this method to industrial-scale stirred tank bioreactors and achieve an unprecedented hPSC amplification rate of 277-fold in 6.5 days. In brief, our findings indicate that our 3D culture system offers a suitable strategy both for basic stem cell biology experiments and for clinical applications.
Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study
Authors: Shijia Zhang, Kimberly Tang, Guihong Wan, Nga Nguyen, Chenyue Lu, Pearl Ugwu-Dike, Neel Raval, Jayhyun Seo, Nora A. Alexander, Ruple Jairath, Jordan Phillipps, Bonnie W. Leung, Kathleen Roster, Wenxin Chen, Leyre Zubiri, Genevieve Boland, Steven T. Chen, Hensin Tsao, Shadmehr Demehri, Nicole R. LeBoeuf, Kerry L. Reynolds, Kun-Hsing Yu, Alexander Gusev, Shawn G. Kwatra, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2023)
Multi-modality data-driven analysis of diagnosis and treatment of psoriatic arthritis
Authors: Jing Xu, Jiarui Ou, Chen Li, Zheng Zhu, Jian Li, Hailun Zhang, Junchen Chen, Bin Yi, Wu Zhu, Weiru Zhang, Guanxiong Zhang, Qian Gao, Yehong Kuang, Jiangning Song, Xiang Chen, Hong Liu
Journal: npj Digital Medicine (2023)

Psoriatic arthritis (PsA) is associated with psoriasis, featured by its irreversible joint symptoms. Despite the significant impact on the healthcare system, it is still challenging to leverage machine learning or statistical models to predict PsA and its progression, or analyze drug efficacy. With 3961 patients' clinical records, we developed a machine learning model for PsA diagnosis and analysis of PsA progression risk, respectively. Furthermore, general additive models (GAMs) and the Kaplan-Meier (KM) method were applied to analyze the efficacy of various drugs on psoriasis treatment and inhibiting PsA progression. The independent experiment on the PsA prediction model demonstrates outstanding prediction performance with an AUC score of 0.87 and an AUPR score of 0.89, and the Jackknife validation test on the PsA progression prediction model also suggests the superior performance with an AUC score of 0.80 and an AUPR score of 0.83, respectively. We also identified that interleukin-17 inhibitors were the more effective drug for severe psoriasis compared to other drugs, and methotrexate had a lower effect in inhibiting PsA progression. The results demonstrate that machine learning and statistical approaches enable accurate early prediction of PsA and its progression, and analysis of drug efficacy.
Adult intracranial ependymoma—relevance of DNA methylation profiling for diagnosis, prognosis, and treatment
Authors: Malte Träger, Leonille Schweizer, Eilís Pérez, Simone Schmid, Elisabeth G Hain, Carsten Dittmayer, Julia Onken, Kohei Fukuoka, Koichi Ichimura, Ulrich Schüller, Lasse Dührsen, Michael Müther, Werner Paulus, Christian Thomas, Marielena Gutt-Will, Philippe Schucht, Theoni Maragkou, Jens Schittenhelm, Franziska Eckert, Maximilian Niyazi, Daniel F Fleischmann, Mario M Dorostkar, Petra Feyer, Sven-Axel May, Dag Moskopp, Harun Badakhshi, Cornelia Radke, Jan Walter, Felix Ehret, David Capper, David Kaul
Journal: Neuro-Oncology (2023)

Abstract Background A methylation-based classification of ependymoma has recently found broad application. However, the diagnostic advantage and implications for treatment decisions remain unclear. Here, we retrospectively evaluate the impact of surgery and radiotherapy on outcome after molecular reclassification of adult intracranial ependymomas. Methods Tumors diagnosed as intracranial ependymomas from 170 adult patients collected from 8 diagnostic institutions were subjected to DNA methylation profiling. Molecular classes, patient characteristics, and treatment were correlated with progression-free survival (PFS). Results The classifier indicated an ependymal tumor in 73.5%, a different tumor entity in 10.6%, and non-classifiable tumors in 15.9% of cases, respectively. The most prevalent molecular classes were posterior fossa ependymoma group B (EPN-PFB, 32.9%), posterior fossa subependymoma (PF-SE, 25.9%), and supratentorial ZFTA fusion-positive ependymoma (EPN-ZFTA, 11.2%). With a median follow-up of 60.0 months, the 5- and 10-year-PFS rates were 64.5% and 41.8% for EPN-PFB, 67.4% and 45.2% for PF-SE, and 60.3% and 60.3% for EPN-ZFTA. In EPN-PFB, but not in other molecular classes, gross total resection (GTR) (P = .009) and postoperative radiotherapy (P = .007) were significantly associated with improved PFS in multivariable analysis. Histological tumor grading (WHO 2 vs. 3) was not a predictor of the prognosis within molecularly defined ependymoma classes. Conclusions DNA methylation profiling improves diagnostic accuracy and risk stratification in adult intracranial ependymoma. The molecular class of PF-SE is unexpectedly prevalent among adult tumors with ependymoma histology and relapsed as frequently as EPN-PFB, despite the supposed benign nature. GTR and radiotherapy may represent key factors in determining the outcome of EPN-PFB patients.
Mild hypothermia attenuates ischaemia/reperfusion injury: insights from serial non-invasive pressure–volume loops
Authors: Jonathan Berg, Robert Jablonowski, David Nordlund, Daniel Ryd, Einar Heiberg, Marcus Carlsson, Håkan Arheden
Journal: Cardiovascular Research (2023)

Mild hypothermia, 32-35°C, reduces infarct size in experimental studies, potentially mediating reperfusion injuries, but human trials have been ambiguous. To elucidate the cardioprotective mechanisms of mild hypothermia, we analysed cardiac performance in a porcine model of ischaemia/reperfusion, with serial cardiovascular magnetic resonance (CMR) imaging throughout 1 week using non-invasive pressure-volume (PV) loops.Normothermia and Hypothermia group sessions (n = 7 + 7 pigs, non-random allocation) were imaged with Cardiovascular magnetic resonance (CMR) at baseline and subjected to 40 min of normothermic ischaemia by catheter intervention. Thereafter, the Hypothermia group was rapidly cooled (mean 34.5°C) for 5 min before reperfusion. Additional CMR sessions at 2 h, 24 h, and 7 days acquired ventricular volumes and ischaemic injuries (unblinded analysis). Stroke volume (SV: -24%; P = 0.029; Friedmans test) and ejection fraction (EF: -20%; P = 0.068) were notably reduced at 24 h in the Normothermia group compared with baseline. In contrast, the decreases were ameliorated in the Hypothermia group (SV: -6%; P = 0.77; EF: -6%; P = 0.13). Mean arterial pressure remained stable in Normothermic animals (-3%, P = 0.77) but dropped 2 h post-reperfusion in hypothermic animals (-18%, P = 0.007). Both groups experienced a decrease and partial recovery pattern for PV loop-derived variables over 1 week, but the adverse effects tended to attenuate in the Hypothermia group. Infarct sizes were 10 ± 8% in Hypothermic and 15 ± 8% in Normothermic animals (P = 0.32). Analysis of covariance at 24 h indicated that hypothermia has cardioprotective properties incremental to reducing infarct size, such as higher external power (P = 0.061) and lower arterial elastance (P = 0.015).Using non-invasive PV loops by CMR, we observed that mild hypothermia at reperfusion alleviates the heart's work after ischaemia/reperfusion injuries during the first week and preserves short-term cardiac performance. This hypothesis-generating study suggests hypothermia to have cardioprotective properties, incremental to reducing infarct size. The primary cardioprotective mechanism was likely an afterload reduction acutely unloading the left ventricle.
Harveian Lectures on Lupus
Authors: J. Hutchinson
Journal: BMJ (1888)

the patient from experience of relief and reprieve, attained by their preceding experience.Four patients died within a few days of the operation, partly from exhaustion, two from cystitis and peritonitis, all among the very early cases, probably from too great an anxiety on my part to remove the whole of the growth, and the want of safer and more efficient instru- ments, which experience has led me now to employ.Two died from blood poisoning, each on the twelfth day after operation, one after the erineal incision, and the other after the removal of a large tumour By the suprapubic route.Several are living with threatening return:the great majority gaining relief from severe symptoms and some extension of life, varying considerably in different instances.We have to remember that every patient with bleeding vesical tumour inevitably succumbs sooner or later to his fate, unless surgical aid is afforded.Every case therefore of permanent cure is a life ab- solutely saved by our art, while prolongation of life, whatever it may amount to, is equally so.Hence these results, although necessarily showinDg many failures to remove the disease, certainly manifest a considerable aggregate of clear gain in the matter of human life, and must be so regarded in relation to the sum total of those who are afflicted.Under these circumstances it is impossible to predict for any in- dividual case the result of operation, even in an approximate degree.Until incision has been made and actual contact with the finger, suf- ficiDg to ascertain the physical characters of the tumour, has been completed, no one can say whether it be possible to remove it com- pletely.If separation is not complete there is not much hope of a permanentcure; nevertheless, I am disposed, after observing the issue of one of my cases which suggested the idea, to think that even when not quite removed there are two processes, almost necessarily follow.ing, which tena to favour a successful issue.The first is, sloughing of a thin layer of the surface left, due to the crushing action of the blunt forceps; secondly, the cicatricial action and contracting of the surface, which probably suffices to strangle and destroy any very slight remains of the papillomatous tissue there.
Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population Commentary: Do genes or environment influence development of rheumatoid arthritis?
Authors: A. J Svendsen
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To determine the relative importance of environmental and genetic effects in the development of rheumatoid arthritis. <b>Design:</b> Historical cohort study with record linkage between a twin registry and the Danish discharge registry as well as the Danish national registry of deaths used to estimate completeness. <b>Setting:</b> Two population based nationwide twin birth cohorts. <b>Participants:</b> 37 338 twins were sent a questionnaire about rheumatic diseases. Self reported rheumatoid arthritis was verified by clinical examination and from medical records. <b>Main outcome measures:</b> The probandwise concordance rate of rheumatoid arthritis in monozygotic and dizygotic twins. <b>Results:</b> The response rate was 84.7%. Rheumatoid arthritis was verified in 13 monozygotic and 36 dizygotic twins. There were no concordant monozygotic twin pairs and two concordant dizygotic twin pairs. Based on capture-recapture methods the probability of ascertainment was 78.3%. The probandwise concordance rate was 0 (95% confidence interval 0 to 24.7) in monozygotic twins and 8.8 (1.9 to 23.7) in dizygotic twins. <b>Conclusion:</b> Genes are of minor importance in the development of rheumatoid arthritis. <h3>What is already known on this topic</h3> Rheumatoid arthritis is a multifactorial disease determined by both genetic and environmental factors Previous twin studies have shown a higher concordance for rheumatoid arthritis in monozygotic than in dizygotic twins, but the results have been biased in favour of genetic effects <h3>What this paper adds</h3> As concordance for rheumatoid arthritis in this study was no more common in monozygotic twins than in dizygotic twins environmental effects may be more important than genetic effects in the development of rheumatoid arthritis
Nutrition and Fitness
Authors: Artemis P. Simopoulos
Journal: JAMA (1989)

Industrialized societies are characterized by an abundant and palatable food supply and a decrease in physical activity at home, at work, and in transportation as a result of modern technology. The average American has a body mass index of 26.6 kg/m<sup>2</sup>, 20% above desirable body weight.<sup>1</sup>Recent surveys show that the US population is getting heavier and the average energy intake has increased.<sup>2</sup> Obesity—the result of either overnutrition (increased energy intake) or a sedentary life-style (decreased energy expenditure)—is characterized by a number of metabolic changes related to lipid metabolism. Obese individuals have elevated serum cholesterol and triglyceride and lower high-density lipoprotein concentrations. These changes increase one's risk for coronary heart disease. There are also changes in carbohydrate metabolism, such as hyperglycemia, hyperinsulinemia, insulin resistance, and decreased norepinephrine production. These findings are similar to the metabolic abnormalities found in persons with non-insulin-dependent diabetes mellitus. In overweight persons, the
High-Fat Diets and Breast Cancer Risk
Authors: Geoffrey R. Howe
Journal: JAMA (1992)

Breast cancer is one of the major public health problems for women in the United States—currently a woman has an average lifetime probability of about 10% of developing the disease. In terms of its etiology, although breast cancer is among the most widely studied of cancers, risk factors that have been identified to date, such as late age at first full-term pregnancy, are not readily amenable to modification and hence prevention. This has served to focus both public and scientific attention on the hypothesis that high dietary fat intake increases risk of breast cancer. Thus, the latest results addressing this hypothesis from the US Nurses' Health Study, which are reported in this issue ofTHE Journal,<sup>1</sup>are of considerable interest. See also p 2037. Three types of epidemiologic studies have provided evidence on the postulated association between fat intake and breast cancer risk. Ecologic studies have shown that there
End-stage Renal Disease Among Silica-Exposed Gold Miners
Authors: Geoffrey M. Calvert
Journal: JAMA (1997)

<h3>Objective.</h3> —To examine the association between silica exposure and end-stage renal disease (ESRD). <h3>Design.</h3> —Retrospective cohort study. <h3>Participants.</h3> —A cohort of 2412 white male gold miners was studied. Eligible gold miners worked underground for at least 1 year between 1940 and 1965 in a South Dakota gold mine and were alive on January 1,1977. Of primary interest was exposure to silica. <h3>Methods.</h3> —The ESRD Program Management and Medical Information System (PMMIS) was used to identify members of the gold mine cohort who had treated ESRD and to create a US rate file for treated ESRD. The ESRD incidence among the gold miners was compared with that in the US population. <h3>Results.</h3> —Based on the 11 cohort members identified with treated ESRD, the risk for ESRD in the cohort was elevated (standardized incidence ratio [SIR], 1.37; 95% confidence interval [CI], 0.68-2.46). The risk was greatest for nonsystemic ESRD (ESRD caused by glomerulonephritis or interstitial nephritis) for which the SIR was 4.22 (95% CI, 1.54-9.19), increasing to 7.70 (95% CI, 1.59-22.48) among workers with 10 or more years of employment underground. <h3>Conclusions.</h3> —To our knowledge this is the first epidemiologic study to examine ESRD incidence in an occupational cohort. This study provides evidence that silica exposure is associated with an increased risk for ESRD, especially ESRD caused by glomerulonephritis. This study also demonstrates the usefulness of the ESRD PMMIS to assess ESRD risk among cohorts exposed to potential nephrotoxins.
Tyrosine-Induced Eye and Skin Lesions
Authors: Lowell A. Goldsmith
Journal: JAMA (1976)

Tyrosine-induced eye and skin lesions in man are an autosomal, recessive, inherited syndrome associated with tyrosinemia, tyrosinuria, and increased urinary excretion of tyrosine metabolites. Patients have mild to severe keratitis and erosive and hyperkeratotic lesions on the palms and soles. The degree of involvement was variable in the small number of patients studied. Mental retardation is frequently a part of the syndrome. A low-tyrosine low-phenylalanine diet lowers blood tyrosine level and leads to healing of the skin and eye lesions. Early dietary treatment may prevent mental retardation. (<i>JAMA</i>236:382-384, 1976)
Examining Product Risk in Context
Authors: Dennis Ross-Degnan
Journal: JAMA (1993)

<h3>Objective.</h3> —To examine changes in the prescribing of analgesics after the market entry and subsequent withdrawal of zomepirac sodium, a nonsteroidal anti-inflammatory drug (NSAID), following repeated reports of zomepirac-related deaths. <h3>Design.</h3> —To evaluate this natural quasi experiment, we conducted time-series analyses to compare prescribing in two cohorts of primary care physicians from July 1980 through September 1983. <h3>Setting.</h3> —Study physicians provided outpatient pharmaceutical care to patients enrolled in the New Jersey Medicaid program. <h3>Participants.</h3> —We identified 260 primary care physicians who provided 10 or more prescriptions for zomepirac (zomepirac prescribers) and 308 who provided 10 or more prescriptions for NSAIDs other than zomepirac (other-NSAID prescribers) in Medicaid during the study period. <h3>Main Outcome Measures.</h3> —Monthly rates of prescribing for zomepirac and several categories of substitute analgesics among Medicaid patients seen by study physicians. <h3>Main Results.</h3> —Zomepirac accounted for a stable 11.0% of analgesic prescribing among the zomepirac-prescriber cohort; label changes and manufacturer product-risk warnings 11 months before the product's withdrawal from the market had no impact on use. After market entry, zomepirac prescribers reduced use of other NSAIDs and propoxyphene (hydrochloride or napsylate) in comparison with other-NSAID prescribers (-8.1% and -2.8% of total analgesic prescribing, respectively;<i>P</i>&lt;.001). After the product's withdrawal from the market, zomepirac prescribers showed significant increases in relative prescribing of other NSAIDs (+6.8%;<i>P</i>&lt;.001), propoxyphene (+2.1%;<i>P</i>&lt;.05), and analgesics containing barbiturates (+2.7%;<i>P</i>&lt;.001). <h3>Conclusions.</h3> —The sudden withdrawal of zomepirac from the market resulted in substitutions not only of other NSAIDs, but also of alternative analgesics that carry risks of habituation and adverse effects. Apparent gains in patient safety resulting from market withdrawal of medications must be evaluated in comparison with risks of medications likely to be substituted. (<i>JAMA</i>. 1993;270:1937-1942)
Marihuana as Medicine
Authors: Lester Grinspoon
Journal: JAMA (1995)

BETWEEN 1840 and 1900, European and American medical journals published more than 100 articles on the therapeutic use of the drug known then as<i>Cannabis indica</i>(or Indian hemp) and now as marihuana. It was recommended as an appetite stimulant, muscle relaxant, analgesic, hypnotic, and anticonvulsant. As late as 1913 Sir William Osler recommended it as the most satisfactory remedy for migraine. Today the 5000-year medical history of cannabis has been almost forgotten. Its use declined in the early 20th century because the potency of preparations was variable, responses to oral ingestion were erratic, and alternatives became available—injectable opiates and, later, synthetic drugs such as aspirin and barbiturates. In the United States, the final blow was struck by the Marihuana Tax Act of 1937. Designed to prevent nonmedical use, this law made cannabis so difficult to obtain for medical purposes that it was removed from the pharmacopeia. It is now
Clinical Lecture on Antiseptic Osteotomy for Ankylosis and Deformity
Authors: R. Barwell
Journal: BMJ (1878)

serted, and the boy placed in bed.About a wineglassful of blood only was lost.January 30th.-Thestitches were removed.February 3rd.-The ligatures were removed.May-i6th.-Hewas discharged convalescent.Three sinuses were together weeping half an ounce of pus per diem.The boy looked fresh and well.[May I 8, I878.* In a paper published in the Edinburghz Medical .7ournalfor December I869, I directed attention to this occasional varying mode of commencement of the fits in the same patient.